Treatment of obesity using non-daily administration of 6-O-(4-dimethylaminoethoxy) cinnamoyl fumagillol

ABSTRACT

The invention generally relates to methods of treating an overweight or obese subject, and treating overweight- or obesity-related conditions using non-daily administration of e.g., a MetAP-2 inhibitor.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.13/990,271, filed May 29, 2013, which is a U.S. national phaseapplication under 35 U.S.C. §371 of International Application No.PCT/US2011/062413, filed Nov. 29, 2011, which claims the benefit of andpriority to U.S. Provisional Patent Application No. 61/417,692, filedNov. 29, 2010, and U.S. Provisional Patent Application No. 61/500,662,filed Jun. 24, 2011, the contents of each of which are herebyincorporated by reference in their entirety.

BACKGROUND

Obesity is a complex medical disorder of appetite regulation andmetabolism resulting in excessive accumulation of adipose tissue mass.Typically defined as a body mass index (BMI) of 30 kg/m² or more,obesity is a world-wide public health concern that is associated withcardiovascular disease, diabetes, certain cancers, respiratorycomplications, osteoarthritis, gallbladder disease, decreased lifeexpectancy, and work disability. The primary goals of obesity therapyare to reduce excess body weight, improve or prevent obesity-relatedmorbidity and mortality, and maintain long-term weight loss.

Treatment modalities typically include diet and exercise programs,lifestyle management, pharmacotherapy, and surgery. Treatment decisionsare made based on severity of obesity, seriousness of associated medicalconditions, patient risk status, and patient expectations. Notableimprovements in cardiovascular risk and the incidence of diabetes havebeen observed with weight loss of 5-10% of body weight, supportingclinical guidelines for the treatment of obesity that recommend a targetthreshold of 10% reduction in body weight from baseline values. Theseimprovements are notable even for patients who may be overweight (with aBMI of 27 kg/m²) but also have a weight related co-morbidity such ashypertension, type 2 diabetes, dyslipidemia, or central adiposity.

However, while prescription anti-obesity medications are typicallyconsidered for selected patients at increased medical risk because oftheir weight and for whom lifestyle modifications (diet restriction,physical activity, and behavior therapy) alone have failed to producedurable weight loss, approved drugs have had unsatisfactory efficacy forseverely obese subjects, leading to only ˜3-5% reduction in body weightafter a year of treatment.

Bariatric surgery may be considered as a weight loss intervention forpatients at or exceeding a BMI of 40 kg/m². Patients with a BMI≧35 kg/m²and an associated serious medical condition are also candidates for thistreatment option. Recently the US-FDA has approved lapband proceduresfor patients exceeding a BMI of 35 kg/m² and for those patients who are30 kg/m² or higher who have at least one obesity-related condition, suchas diabetes. Unfortunately, postoperative complications commonly resultfrom bariatric surgical procedures, including bleeding, embolism orthrombosis, wound complications, deep infections, pulmonarycomplications, and gastrointestinal obstruction; reoperation during thepostoperative period is sometimes necessary to address thesecomplications. Rates of reoperation or conversion surgery beyond thepostoperative period depend on the type of bariatric procedure, and inone study ranged from 17% to 31%. Intestinal absorptive abnormalities,such as micronutrient deficiency and protein-calorie malnutrition, alsoare typically seen with bypass procedures, requiring lifelong nutrientsupplementation. Major and serious adverse outcomes associated withbariatric surgery are common, observed in approximately 4 percent ofprocedures performed (including death in 0.3 to 2 percent of allpatients receiving laparoscopic banding or bypass surgeries,respectively)

MetAP2 encodes a protein that functions at least in part byenzymatically removing the amino terminal methionine residue fromcertain newly translated proteins such as glyceraldehyde-3-phosphatedehydrogenase (Warder et al. (2008) J Proteome Res 7:4807). Increasedexpression of the MetAP2 gene has been historically associated withvarious forms of cancer. Molecules inhibiting the enzymatic activity ofMetAP2 have been identified and have been explored for their utility inthe treatment of various tumor types (Wang et al. (2003) Cancer Res.63:7861) and infectious diseases such as microsporidiosis,leishmaniasis, and malaria (Zhang et al. (2002) J. Biomed. Sci. 9:34).However, such MetAP2 inhibitors may be useful as well for patients withexcess adiposity and conditions related to adiposity including type 2diabetes, hepatic steatosis, and cardiovascular disease (via e.g.ameliorating insulin resistance, reducing hepatic lipid content, andreducing cardiac workload). Methods of treating obese subjects that aremore effective than e.g. dieting alone are clearly needed.

SUMMARY OF THE INVENTION

This disclosure generally relates to methods of treating an overweightor obese subject or patient that include non-daily administration of apharmaceutically effective amount of a MetAP2-inhibitor, such as6-O-(4-dimethylaminoethoxy)cinnamoyl fumagillol or pharmaceuticallyacceptable salts thereof, to a patient in need thereof, e.g., a human ora companion animal such as a cat or a dog. For example, a method fortreating obesity or for reducing body weight in a patient in needthereof is provided, comprising administering to the patient, on a lessthan daily basis, a dose of a formulation comprising a therapeuticallyeffective amount of a compound 6-O-(4-dimethylaminoethoxy)cinnamoylfumagillol or pharmaceutically acceptable salts thereof. Such a method,upon a single initial administration of a dose or after administrationof two doses, may provide the patient with a body weight loss of about0.3 to about 2 kg of the initial patient weight. Such a disclosed methodmay provide a well tolerated rate of weight loss of about 1 to about1.5% of the initial patient weight per week.

Contemplated methods may include administering to the patient a singledose of a disclosed formulation about every other day, twice weekly,about once a week, about once every other week, and/or about once ortwice a month.

A method for treating obesity or for reducing body weight in a patientin need thereof is provided herein that includes administering to thepatient a dose of a formulation comprising a therapeutically effectiveamount of a compound 6-O-(4-dimethylaminoethoxy)cinnamoyl fumagillol orpharmaceutically acceptable salts thereof, for a first period of time,withheld for a second period of time, and again administered for a thirdperiod of time, wherein the therapeutically effective amount providesthe patient with a body weight loss of for example, about 1% to about 2%initial patient weight per week (and/or provides for a body weight lossof about 0.5 kg to about 2 kg or more) after the first period of time. Afirst period of time may be selected from the group consisting of daily,every other day, every three, four or five days, twice weekly, ormonthly. A second period of time may be selected from the groupconsisting of one, two, three, four, five, or six days, one, two, three,four, or five weeks, and one month. A third period of time may beselected from daily, every other day, every three, four or five days,twice weekly, monthly, or every other month.

Contemplated doses may include therapeutically effective amount of thedisclosed compound of e.g., about 0.5 mg/m² to about 3 mg/m² (based on apatient's actual or calculated surface area), e.g. about 0.9 mg/m² toabout 1.5 mg/m², e.g., about 1.25, 1.5, 2 or 3 mg/m². In otherembodiments, a therapeutically effective amount of a disclosed compoundmay be at least about 20 to about 80 μg per kg, or at least about of 20to about 40 μg per kg excess body weight of the patient. For example, atherapeutically effective amount of a disclosed compound, e.g.,administered every three or four days may be a dosage that includese.g., about 1.8 mg, 2.5 mg, 2 mg, 3 mg, 4 mg, 5 mg, or 6 mg of adisclosed compound. Administration of a single dose with such a methodmay reduce weight in the patient for at least three or four days, or upto seven days, for example, even without further administration.

Disclosed methods may include maintaining from 0 to 0.3 ng/mL of thecompound in the plasma of a patient for at least 12 hours to 24 hours ormore after administration of a dose, but for example, no longer thanabout 36 hours after administration. It may be understood that disclosedmethods may include repeatedly administering to the patient an effectivedose on a less than daily basis until a desired weight is achieved.

For example, provided herein is a method for treating obesity or forreducing body weight in a patient in need thereof, comprisingadministering to the patient a dose comprising about 0.9 mg/m² or more(e.g., about 0.75 mg/m² to about 3 mg/m²), of a compound6-O-(4-dimethylaminoethoxy)cinnamoyl fumagillol or pharmaceuticallyacceptable salts thereof, wherein, for example, a single administrationof the dose reduces weight in the patient for at least three days or atleast four days.

Disclosed methods may include administering about 20 μg to about 80 μgof the compound per excess body weight of the patient. For example, amethod for treating obesity or for reducing body weight is provided thatcomprises administering to a patient in need thereof at least about 30μg or at least about 40 μg (e.g., at least about 40 μg to about 60 μg)of 6-O-(4-dimethylaminoethoxy)cinnamoyl fumagillol or pharmaceuticallyacceptable salts thereof per kg of excess adipose tissue of the patient.In an embodiment, a method of reducing the body weight of a patient inneed thereof for at least four days is provided comprising administeringto the patient a single dose of at least about 20 μg of6-O-(4-dimethylaminoethoxy)cinnamoyl fumagillol or pharmaceuticallyacceptable salts thereof, per kg of excess adipose tissue of thepatient. Such a method may further comprises administering a second dose(e.g., at intervals of two, three or four days or more) of at leastabout 40 μg of 6-O-(4-dimethylaminoethoxy)cinnamoyl fumagillol orpharmaceutically acceptable salts thereof, per kg of excess body weightof the patient at least about 2 days after administration of the singledose. A disclosed method may further comprise administering subsequentdoses at intervals of between about 4 days and 1 month, and/or maycomprise maintaining about 0 to about 0.3 ng/mL of the compound in theplasma of a patient for 24 hours after administration, e.g., for about24 to about 36 hours after administration.

A method for treating obesity or for reducing body weight in a patientin need thereof is also provided comprising administering to thepatient, on a less than daily basis, a dose of a formulation comprisinga therapeutically effective amount of a compound6-O-(4-dimethylaminoethoxy)cinnamoyl fumagillol or pharmaceuticallyacceptable salts thereof, wherein the method produces lesstestes-related toxicity as compared to a patient administered the doseon a daily basis.

In some embodiments, a disclosed method may provide, uponadministration, adiponectin levels in the patient that are increased byat least 50% above the adiponectin level in the patient beforeadministration. Contemplated human patients may have an initial bodymass index of at least about 27 kg/m², at least about 30 kg/m², or atleast about 35, or at least about 40 kg/m². Administering ascontemplated herein may comprise subcutaneous administration orintravenous administration.

For example, provided herein is a method for treating obesity in apatient having an initial body mass index of at least about 30 kg/m²,comprising administering to the patient (e.g. human), on a less thandaily basis (e.g. twice weekly, weekly, or every 3 or 4 days) a dose ofa formulation comprising a therapeutically effective amount of acompound 6-O-(4-dimethylaminoethoxy)cinnamoylfumagillol orpharmaceutically acceptable salts thereof, as well as a method forreducing the weight of a patient (e.g. human) having an initial bodymass index of at least about 27 kg/m², and suffering from weight relatedco-morbidity (e.g., hypertension, type 2 diabetes, dyslipidemia, and/orcentral adiposity), comprising administering to the patient, on a lessthan daily basis e.g. twice weekly, weekly, or every 3 or 4 days, a doseof a formulation comprising a therapeutically effective amount of acompound 6-O-(4-dimethylaminoethoxy)cinnamoylfumagillol orpharmaceutically acceptable salts thereof. The dose comprises about 0.5mg/m² to about 1.5 mg/m² of the compound, or about 30 μg to about 90 μgof the compound per kilogram of excess body weight of the patient, about20 μg to 60 μg about per kilogram of ideal body weight of the patient,or 1.5 to about 6.0 mg of the free base of the compound.

Also provided herein is a pharmaceutically acceptable formulationcomprising a compound 6-O-(4-dimethylaminoethoxy)cinnamoyl fumagillol orpharmaceutically acceptable salts thereof; wherein a single doseparenteral administration of the formulation to a human patient producesa peak plasma concentration (C_(max)) of about 0.5 to about 14 ng/m, ora peak plasma concentration may be about 0.5 to about 6 ng/mL. In someembodiments, the minimum plasma concentration (C_(min)) 24 hours afterthe administration is about 0 to about 0.3 ng/mL. In an embodiment, theminimum plasma concentration in a patient 36 hours after administrationis de minimus, or not detectable, e.g. about 0 ng/mL.

A pharmaceutically acceptable formulation is contemplated that includesa compound 6-O-(4-dimethylaminoethoxy)cinnamoyl fumagillol orpharmaceutically acceptable salts thereof; wherein a single doseparenteral (e.g. intravenous or subcutaneous) administration of theformulation to a human patient produces a minimum plasma concentration(C_(min)) 24 hours after administration of about 0 to about 0.3 ng/mL.Such single dose administration to a human may produce a mean area underthe curve concentration of the compound of (AUC (0-24 hours) of about 6to about 30 ng hr/mL, or about 8.6 to about 13.9 ng hr/mL.

BRIEF DESCRIPTION OF FIGURES

FIG. 1 depicts body weight change (percent) with twice weekly dosing of0.1 mg/m², 0.3 mg/m², and 0.9 mg/m² (approximately 1.8 to 2.1 mg) of6-O-(4-dimethylaminoethoxy)cinnamoyl fumagillol in human patients.Values are means±SEM (n=6 per dose level study); p values derived from2-way ANOVA with Bonferroni post-test comparisons (*, p<0.05; **,p<0.01; ***, p<0.001 vs. placebo).

FIG. 2 depicts visual analogue scale of hunger decline by approximately50% with body weight change (percent) with twice weekly dosing off 0.1mg/m², 0.3 mg/m², and 0.9 mg/m² (approximately 1.8 to 2.1 mg) of6-O-(4-dimethylaminoethoxy)cinnamoyl fumagillol in human patients.Values are means (n=6 per dose level) of changes in fasted Visual AnalogScale scores for each visit day vs. Day 1 for population; p valuesderived from 2-way ANOVA with Bonferroni post-test comparisons (*,p<0.05; **, p<0.01 vs. placebo).

FIG. 3 depicts dose exposure stability. Y-axis is plasma concentrationof compound in ng/mL trials of participants receiving 0.9 mg/m².

FIG. 4 shows average pharmacokinetic (PK) profile with dose (ng/ml) ofdrug at day 26 of trials participants receiving 0.1, 0.3 and 0.9 mg/m².

FIG. 5 depicts correlation of weight change and exposure of drug at 24hours.

FIG. 6 depicts the body weight change (kg) as a function of a μg per kgexcess weight dose of 6-O-(4-dimethylaminoethoxy)cinnamoyl fumagillol inobese human patients. X axis is dose of compound (μg/kg of excessiveweight).

FIG. 7 depicts weight change in patients administered a twice a weekdose of 6-O-(4-dimethylaminoethoxy)cinnamoyl fumagillol, with varieddosage amounts. Weight loss plateaus at 0.9 mg/m² (˜1.8 mg dose)administered twice weekly, with a maximum efficacy obtained with a doseadministered biweekly of ˜20 μg/kg.

FIG. 8 depicts the correlation between adiponectin changes and excessweight loss after administration of the disclosed MetAP-2 inhibitor inhuman obese patients.

FIG. 9 depicts the effect of administration of the disclosed MetAP-2inhibitor on the ratio of leptin to adiponectin serum levels in humanobese patients after administration.

FIG. 10 depicts the seminal vesicle weight and testes weight in ratsafter daily or every three days indicating a less than daily dosingsafety window.

DETAILED DESCRIPTION Overview

The disclosure in part relates to treatment of e.g., obesity using lessthan daily dosing and arises in part due to the unexpected discoverythat the effectiveness of the drug remains for several days afteradministration of an initial dose, even though the half life of the drugis shorter than one day, together with the additional unexpecteddiscovery that dosing and/or effectiveness of the drug depends on theamount of excess body weight of an overweight patient, rather than totalbody weight of the patient.

Obesity and being overweight refer to an excess of fat in proportion tolean body mass. Excess fat accumulation is associated with increase insize (hypertrophy) as well as number (hyperplasia) of adipose tissuecells. Obesity is variously measured in terms of absolute weight,weight:height ratio, degree of excess body fat, distribution ofsubcutaneous fat, and societal and esthetic norms. A common measure ofbody fat is Body Mass Index (BMI). The BMI refers to the ratio of bodyweight (expressed in kilograms) to the square of height (expressed inmeters). Body mass index may be accurately calculated using theformulas: SI units: BMI=weight(kg)/(height²(m²), or US units:BMI=(weight(lb)*703)/(height²(in²).

In accordance with the U.S. Centers for Disease Control and Prevention(CDC), an overweight adult has a BMI of 25 kg/m² to 29.9 kg/m², and anobese adult has a BMI of 30 kg/m² or greater. A BMI of 40 kg/m² orgreater is indicative of morbid obesity or extreme obesity. Forchildren, the definitions of overweight and obese take into account age,stature, and gender as they relate to what are appropriate amounts ofbody fat and do not strictly rely upon BMI calculations.

BMI does not account for the fact that excess adipose can occurselectively in different parts of the body, and development of adiposetissue can be more dangerous to health in some parts of the body ratherthan in other parts of the body. For example, “central obesity”,typically associated with an “apple-shaped” body, results from excessadiposity especially in the abdominal region, including belly fat, andintra-abdominal, or visceral fat, and carries higher risk ofco-morbidity than “peripheral obesity”, which is typically associatedwith a “pear-shaped” body resulting from excess adiposity especially onthe hips. Measurement of waist/hip circumference ratio (WHR) can be usedas an indicator of central obesity. A minimum WHR indicative of centralobesity has been variously set, and a centrally obese adult typicallyhas a WHR of about 0.85 or greater if female and about 0.9 or greater ifmale. Methods of determining whether a subject is overweight or obesethat account for the ratio of excess adipose tissue to lean body massmay involve obtaining a body composition of the subject. Bodycomposition can be obtained by measuring the thickness of subcutaneousfat in multiple places on the body, such as the abdominal area, thesubscapular region, arms, buttocks and thighs. These measurements arethen used to estimate total body fat with a margin of error ofapproximately four percentage points. Another method is bioelectricalimpedance analysis (BIA), which uses the resistance of electrical flowthrough the body to estimate body fat.

Another method is using a large tank of water to measure body buoyancy.Increased body fat will result in greater buoyancy, while greater musclemass will result in a tendency to sink. Yet another method is fan-beamdual energy X-ray absorptiometry (DEXA). DEXA allows body composition,particularly total body fat and/or regional fat mass, to be determinednon-invasively.

Excess body weight may be assessed, for example, by comparing the weightof a patient in need of treatment to the weight of the same patient thatwould achieve a desired, e.g. non-obese, BMI (e.g. a desired BMI ofabout 25 or less). For example, excess body weight of a 1.6 m patientweighing 89.6 kg (and having a BMI of 35) may be found by calculatingthe weight required for a BMI of 25 (i.e., about 64 kg); the initialexcess body weight of such patient would about 89.6−64=25.6 kg. Idealbody weight can be assessed, for example, by calculating 25*(height ofpatient)², or e.g., by consulting Metropolitan or other life insurancetables.

Methods

A method for treating obesity or for reducing body weight in a patientin need thereof is provided herein, comprising administering to thepatient, on a less than daily basis, a dose of a formulation comprisinga therapeutically effective amount of a compound6-O-(4-dimethylaminoethoxy)cinnamoyl fumagillol or pharmaceuticallyacceptable salts thereof. Such methods may include administering to thepatient a single dose of the formulation about every other day (e.g.every 2 days); twice weekly (e.g. every 3 days, every 4 days, every 5days, every 6 days, or e.g. administered with an interval of about 2 toabout 3 days between doses), once a week, every other week, twicemonthly, once a month or even less often. In some embodiments,contemplated methods include administering a single dose no more thantwice weekly, e.g. no more than every other day or e.g., every thirdday. It may be appreciated that methods that include administering asingle dose on a less frequent basis, may, in some embodiments, be amethod directed to maintaining a specific weight, such as a more optimalbody weight after treatment using other methods disclosed herein.Disclosed methods may include administering a dose of a disclosedcompound on a less than daily basis until a desired weight is achieved.

In another embodiment, provided herein is a method for treating obesityor for reducing body weight in a patient in need thereof, comprisingadministering to the patient a dose of a formulation comprising atherapeutically effective amount of a compound6-O-(4-dimethylaminoethoxy)cinnamoyl fumagillol or pharmaceuticallyacceptable salts thereof, for a first period of time, withheld for asecond period of time, and again optionally administered for a thirdperiod of time, e.g., alternate dosing regimens. For example, for thefirst period of time a patient may be administered a disclosedformulation daily, every other day, every three, four or five days,twice weekly, weekly, twice monthly, monthly, or yearly; during thesecond period of time (e.g. 1 day, 1 week, 2 weeks, 1 month) no dose isadministered; and during e.g. a third period of time, the patient may beadministered on a regimen similar or different to the first period oftime, for example, every other day, every three, four or five days,biweekly, monthly, or yearly. At each administration or period time, theroute of administration may be different or the same as another periodof time.

A method for treating obesity or for reducing body weight in a patientin need thereof is also provided comprising administering to thepatient, on a less than daily basis, a dose of a formulation comprisinga therapeutically effective amount of a compound6-O-(4-dimethylaminoethoxy)cinnamoyl fumagillol or pharmaceuticallyacceptable salts thereof, wherein the method produces lesstestes-related toxicity as compared to a patient administered the doseon a daily basis. For example, disclosed methods of administering asingle dose of a disclosed compound on a less than daily basis may haveno (or minimal) testicular tissue (e.g. seminal vesicle or testes) weigheffects, while daily administration (of e.g., the same single dose) mayresult in testicular lesions and/or organ weight effects.

For example, provided herein, in an embodiment, is a method for treatingobesity in a patient having an initial body mass index of at least about30 kg/m², comprising administering a dose of the disclosed compound, ona less than daily basis (e.g., every three or four days, or twiceweekly) to the patient. In another embodiment, provided herein is amethod for reducing the weight of a patient having an initial body massindex of about 27 kg/m² and a co-morbidity, comprising administering adose of the disclosed compound, on a less than daily basis (e.g., everythree or four days, or twice weekly) to the patient. Such methods mayprovide for weight loss by the patient of about 1 kg to 1.5 kg per week.Contemplated doses, administered on a less than daily basis, may be afixed dose, for example, about 1 mg, 2 mg, 1.5 mg, 1.8 mg, 2.5 mg, 3.0mg, 4 mg, 5 mg or even 6 mg.

The therapeutically effective amount administered in the disclosedmethods such as those above may provide a patient with a body weightloss of about 0.3% to about 2%, about 0.4% to about 2%, or about 0.5% toabout 2% or more, or about 0.5 kg to about 2 kg or more of the initialpatient weight even after an initial dose, or after administration oftwo doses, or after administering after an first period of time, e.g.,such methods may incur weight loss for three or four days or more afteradministration (e.g. parenteral (for example intravenous)administration) of a single dose. For example, a patient, afterreceiving a first dose and/or after receiving a subsequent dose, maycontinue to lose weight for three or four days or more without furtheradministration of a disclosed compound. In some embodiments,administration of an initial first dose, or administration of a firstand second dose (e.g., both administered in the same week), may provideabout 0.5 kg to about 2 kg or more of weight loss. Subsequentadministration may result in further weight loss, until a target patientweight is achieved.

Therapeutically effective doses may be calculated, for example, on thebasis of body surface area (BSA), which can be determined using formulaesuch as those described by Mosteller (Mosteller R D, N Engl J Med 1987Oct. 22; 317(17):1098), in which BSA is calculated in SI units as BSA(m²)=([Height(cm)×Weight(kg)]/3600)^(1/2) (e.g. BSA=SQRT((cm*kg)/3600)),or US units, in which BSA (m²)=([Height(in)×Weight(lbs)]/3131)^(1/2). Insome embodiments, the therapeutically effective amount administered(e.g., intravenously) to patient using a disclosed method is about 0.5mg/m² to about 1.5 mg/m², or about 0.9 mg/m² (or approximately 10 to 20μg per kilo of total body weight) or more of a disclosed compound. Inother embodiments, a therapeutically effective amount is based on excessbody weight (or excess adipose tissue), for example, at least about 30μg of a disclosed compound per kg of excess adipose tissue, (or excessbody weight) of the patient, or least about 40 μg per kg or more ofexcess adipose tissue, (or excess body weight) of the patient, e.g.,about 30 μg per kg of excess adipose tissue (or excess body weight) toabout 60 μg per kg, about 40 μg per kg to about 60 μg per kg, or about35 μg per kg to about 45 μg per kg, or about 35 μg per kg to about 50 μgper kg of excess adipose tissue (or excess body weight).

For example, provided herein is a method for treating obesity or forreducing body weight in a patient in need thereof, comprisingadministering to the patient a dose comprising about 0.9 mg/m² or more(about 0.75 mg/m² to about 3 mg/m², or about 0.9 mg/m² to about 1.5mg/m²) (e.g., administered intravenously) of a compound6-O-(4-dimethylaminoethoxy)cinnamoyl fumagillol or pharmaceuticallyacceptable salts thereof, wherein a single administration of the dosereduces weight in the patient for at least four days.

In another embodiment, a method of treating obesity in a patient in needthereof is provided, comprising administering an effective amount of aMetAP-2 inhibitor, wherein the effective amount is proportional toexcess body weight of said patient. For example, in some embodiments,such effective amount may not be proportional to total body weight. Amethod of treating obesity in a patient in need thereof is alsoprovided, comprising determining the excess body weight or excessadipose tissue of said patient; determining an effective dose of aMetAP-2 based on the excess body weight or adipose tissue for saidpatient; and administering the effective dose to said patient.

For example, provided herein is a method for treating obesity or forreducing body weight, comprising administering to a patient in needthereof at least about 20 μg, 30 μg, or at least about 40 μg or more(e.g., about 20 μg to about 80 μg, or about 40 μg to about 60 μg) of6-O-(4-dimethylaminoethoxy)cinnamoyl fumagillol or pharmaceuticallyacceptable salts thereof per kg of excess adipose tissue (or excess bodyweight) or, in other embodiments, about 0.9 mg/m² (e.g., of calculatedsurface area), or more (e.g., about 0.75 mg/m² to about 3 mg/m²), of thepatient.

In another embodiment, a method of treating obesity or for reducing bodyweight is provided comprising administering a dose, on a less thanweekly basis, of 6-O-(4-dimethylaminoethoxy)cinnamoyl fumagillol orpharmaceutically acceptable salts wherein the doses comprises at leastabout 35 μg to about 75 μg per kilogram, about 20 to about 60 μg/kgideal body weight, or about 20 to about 40 μg/kg of the compound perideal body weight of the patient, wherein ideal body weight is25*(patient height in meters).

Disclosed methods may reduce the body weight of the patient for at least3 or at least 4 days after administration, or at least 7 days afteradministration, at least 14 days after administration, or even at least1 month after administration, e.g., without further administration ofthe compound during that time. It is understood that even though anadministration may provide for weight loss e.g. at least for 3 or 4days, a disclosed compound may be administered more frequently, e.g.every other day.

For example, provided herein is a method of reducing the body weight ofa patient in need thereof for at least four days, comprisingadministering (e.g., parenterally administering) to the patient a singledose of at least about 40 μg of 6-O-(4-dimethylaminoethoxy)cinnamoylfumagillol or pharmaceutically acceptable salts thereof, per kg ofexcess adipose tissue of the patient. In some embodiments, such methodsmay further include administering a second dose of at least about 20 μgof 6-O-(4-dimethylaminoethoxy)cinnamoyl fumagillol or pharmaceuticallyacceptable salts thereof, per kg of excess body weight of the patient(or, in other embodiments, about 0.9 mg/m² or more (or about 0.75 mg/m²to about 3 mg/m²) at least about 4 days after administration of thesingle dose. A second dose, for example, may be administered atintervals of three or four days or more. In another embodiments,disclosed methods may further include administering subsequent doses ofa MetAP2 inhibitor (e.g. —O-(4-dimethylaminoethoxy)cinnamoyl fumagillol)at intervals of between about 4 days and 1 month. Such disclosed methodsmay, upon administration, increase the adiponectin levels of the patientby at least 50% above, or at least 20%, at least 30% at least 40%, ormore, e.g. at least about 20% to about 60% above the adiponectin levelin the patient before administration (e.g. baseline adiponectin of thepatient before treatment.)

In another aspect, a method of treating obesity in a patient in needthereof is provided comprising administering to a patient an effectiveamount of an MetAP-2 inhibitor, wherein the effective amount is capableof increasing adiponectin levels in the patient by at least 50% above,at least 60% above, or at least 20%, at least 30% at least 40%, or more,e.g. at least about 20% to about 60%, or the adiponectin level in thepatient before administration of the inhibitor. Such an effective amountof the MetAP-2 inhibitor may reduce the ratio of leptin to adiponectinplasma levels in the patient after administration. Further,therapeutically effective doses contemplated herein will not typicallyinduce any clinically significant anti-angiogenic action.

Also provided herein is a method of optimizing weight loss in a patientundergoing weight loss treatment, comprising a) administering an amountof a MetAP-2 inhibitor to said patient; b) determining the increase inadiponectin in said patient; and c) increasing the amount of the MetAP-2inhibitor administered to the patient if the change in adiponectin inthe patient is less than an increase of about 60% or more (or 50% ormore, e.g. 30% to about 60% as compared to the adiponectin level of thepatient before administration of the MetAP-2 inhibitor.

In another embodiment, a method of optimizing weight loss in a patientundergoing weight loss treatment, comprising a) administering an amountof a MetAP-2 inhibitor to said patient; b) determining the increase inadiponectin in said patient; c) increasing the amount of the MetAP-2inhibitor administered to the patient if a reduction in the ratio ofleptin to adiponectin in the plasma of the patient is not greater than50%, or not greater than 40%, e.g., the reduction of the ratio of leptinto adiponection is reduced by about 10%, 20%, 30% or 40%.

Contemplated patients include humans or companion animals (e.g. dog orcat). In some embodiments, patients may be female (e.g., in anembodiment, women of non-child bearing potential) or male (e.g., in anembodiment, surgically or biologically sterile males).

In addition to being overweight or obese, a patient may be sufferingfrom other overweight- or obesity-related co-morbidities, i.e., diseasesand other adverse health conditions associated with, exacerbated by, orprecipitated by being overweight or obese. Because being overweight orobese is associated with other adverse health conditions orco-morbidities, for example diabetes, administering a disclosed MetAP2inhibitor may bring a benefit in ameliorating, arresting development ofor, in some cases, even eliminating, these overweight- orobesity-related conditions or co-morbidities. For example, contemplatedmethods of reducing body weight disclosed herein includes treatmentthose patients who have e.g., a BMI of greater than 27 kg/m², and whohave one or more weight related co-morbidities, such as hypertension,type 2 diabetes, dyslipidemia, and/or central adiposity.

In some embodiments, methods provided herein may further includeadministering at least one other agent in addition to a disclosed MetAP2inhibitor, e.g., an agent directed to treatment of these overweight- orobesity-related conditions.

Contemplated other agents include those administered to treat type 2diabetes such as sulfonylureas (e.g., chlorpropamide, glipizide,glyburide, glimepiride); meglitinides (e.g., repaglinide andnateglinide); biguanides (e.g., metformin); thiazolidinediones(rosiglitazone, troglitazone, and pioglitazone); glucagon-like 1 peptidemimetics (e.g. exenatide and liraglutide); sodium-glucose cotransporterinhibitors (e.g., dapagliflozin), renin inhibitors, andalpha-glucosidase inhibitors (e.g., acarbose and meglitol), and/or thoseadministered to treat cardiac disorders and conditions, suchhypertension, dyslipidemia, ischemic heart disease, cardiomyopathy,cardiac infarction, stroke, venous thromboembolic disease and pulmonaryhypertension, which have been linked to overweight or obesity, forexample, chlorthalidone; hydrochlorothiazide; indapamide, metolazone;loop diuretics (e.g., bumetanide, ethacrynic acid, furosemide, lasix,torsemide); potassium-sparing agents (e.g., amiloride hydrochloride,spironolactone, and triamterene); peripheral agents (e.g., reserpine);central alpha-agonists (e.g., clonidine hydrochloride, guanabenzacetate, guanfacine hydrochloride, and methyldopa); alpha-blockers(e.g., doxazosin mesylate, prazosin hydrochloride, and terazosinhydrochloride); beta-blockers (e.g., acebutolol, atenolol, betaxolol,nisoprolol fumarate, carteolol hydrochloride, metoprolol tartrate,metoprolol succinate, Nadolol, penbutolol sulfate, pindolol, propranololhydrochloride, and timolol maleate); combined alpha- and beta-blockers(e.g., carvedilol and labetalol hydrochloride); direct vasodilators(e.g., hydralazine hydrochloride and minoxidil); calcium antagonists(e.g., diltiazem hydrochloride and verapamil hydrochloride);dihydropyridines (e.g., amlodipine besylate, felodipine, isradipine,nicardipine, nifedipine, and nisoldipine); ACE inhibitors (benazeprilhydrochloride, captopril, enalapril maleate, fosinopril sodium,lisinopril, moexipril, quinapril hydrochloride, ramipril, trandolapril);angiotensin II receptor blockers (e.g., losartan potassium, valsartan,and Irbesartan); and combinations thereof, as well as statins such asmevastatin, lovastatin, pravastatin, simvastatin, velostatin,dihydrocompactin, fluvastatin, atorvastatin, dalvastatin, carvastatin,crilvastatin, bevastatin, cefvastatin, rosuvastatin, pitavastatin, andglenvastatin, typically for treatment of dyslipidemia.

Other agents that may be co-administered (e.g. sequentially orsimultaneously) include agents administered to treat ischemic heartdisease including statins, nitrates (e.g., Isosorbide Dinitrate andIsosorbide Mononitrate), beta-blockers, and calcium channel antagonists,agents administered to treat cardiomyopathy including inotropic agents(e.g., Digoxin), diuretics (e.g., Furosemide), ACE inhibitors, calciumantagonists, anti-arrhythmic agents (e.g., Sotolol, Amiodarone andDisopyramide), and beta-blockers, agents administered to treat cardiacinfarction including ACE inhibitors, Angiotensin II receptor blockers,direct vasodilators, beta blockers, anti-arrhythmic agents andthrombolytic agents (e.g., Alteplase, Retaplase, Tenecteplase,Anistreplase, and Urokinase), agents administered to treat strokesincluding anti-platelet agents (e.g., Aspirin, Clopidogrel,Dipyridamole, and Ticlopidine), anticoagulant agents (e.g., Heparin),and thrombolytic agents, agents administered to treat venousthromboembolic disease including anti-platelet agents, anticoagulantagents, and thrombolytic agents, agents administered to treat pulmonaryhypertension include inotropic agents, anticoagulant agents, diuretics,potassium (e.g., K-dur), vasodilators (e.g., Nifedipine and Diltiazem),Bosentan, Epoprostenol, and Sildenafil, agents administered to treatasthma include bronchodilators, anti-inflammatory agents, leukotrieneblockers, and anti-Ige agents. Particular asthma agents includeZafirlukast, Flunisolide, Triamcinolone, Beclomethasone, Terbutaline,Fluticasone, Formoterol, Beclomethasone, Salmeterol, Theophylline, andXopenex, agents administered to treat sleep apnea include Modafinil andamphetamines, agents administered to treat nonalcoholic fatty liverdisease include antioxidants (e.g., Vitamins E and C), insulinsensitizers (Metformin, Pioglitazone, Rosiglitazone, and Betaine),hepatoprotectants, and lipid-lowering agents, agentsadministered totreat osteoarthritis of weight-bearing joints include Acetaminophen,non-steroidal anti-inflammatory agents (e.g., Ibuprofen, Etodolac,Oxaprozin, Naproxen, Diclofenac, and Nabumetone), COX-2 inhibitors(e.g., Celecoxib), steroids, supplements (e.g. glucosamine andchondroitin sulfate), and artificial joint fluid, agents administered totreat Prader-Willi Syndrome include human growth hormone (HGH),somatropin, and weight loss agents (e.g., Orlistat, Sibutramine,Methamphetamine, Ionamin, Phentermine, Bupropion, Diethylpropion,Phendimetrazine, Benzphetermine, and Topamax), agents administered totreat polycystic ovary syndrome include insulin-sensitizers,combinations of synthetic estrogen and progesterone, Spironolactone,Eflornithine, and Clomiphene, agents administered to treat erectiledysfunction include phosphodiesterase inhibitors (e.g., Tadalafil,Sildenafil citrate, and Vardenafil), prostaglandin E analogs (e.g.,Alprostadil), alkaloids (e.g., Yohimbine), and testosterone, agentsadministered to treat infertility include Clomiphene, Clomiphenecitrate, Bromocriptine, Gonadotropin-releasing Hormone (GnRH), GnRHagonist, GnRH antagonist, Tamoxifen/nolvadex, gonadotropins, HumanChorionic Gonadotropin (HCG), Human Menopausal Gonadotropin (HmG),progesterone, recombinant follicle stimulating hormone (FSH),Urofollitropin, Heparin, Follitropin alfa, and Follitropin beta, agentsadministered to treat obstetric complications include Bupivacainehydrochloride, Dinoprostone PGE2, Meperidine HCl,Ferro-folic-500/iberet-folic-500, Meperidine, Methylergonovine maleate,Ropivacaine HCl, Nalbuphine HCl, Oxymorphone HCl, Oxytocin,Dinoprostone, Ritodrine, Scopolamine hydrobromide, Sufentanil citrate,and Oxytocic, agents administered to treat depression include serotoninreuptake inhibitors (e.g., Fluoxetine, Escitalopram, Citalopram,Paroxetine, Sertraline, and Venlafaxine); tricyclic antidepressants(e.g., Amitriptyline, Amoxapine, Clomipramine, Desipramine, Dosulepinhydrochloride, Doxepin, Imipramine, Iprindole, Lofepramine,Nortriptyline, Opipramol, Protriptyline, and Trimipramine); monoamineoxidase inhibitors (e.g., Isocarboxazid, Moclobemide, Phenelzine,Tranylcypromine, Selegiline, Rasagiline, Nialamide, Iproniazid,Iproclozide, Toloxatone, Linezolid, Dienolide kavapyronedesmethoxyyangonin, and Dextroamphetamine); psychostimulants (e.g.,Amphetamine, Methamphetamine, Methylphenidate, and Arecoline);antipsychotics (e.g., Butyrophenones, Phenothiazines, Thioxanthenes,Clozapine, Olanzapine, Risperidone, Quetiapine, Ziprasidone,Amisulpride, Paliperidone, Symbyax, Tetrabenazine, and Cannabidiol); andmood stabilizers (e.g., Lithium carbonate, Valproic acid, Divalproexsodium, Sodium valproate, Lamotrigine, Carbamazepine, Gabapentin,Oxcarbazepine, and Topiramate), agents administered to treat anxietyinclude serotonin reuptake inhibitors, mood stabilizers, benzodiazepines(e.g., Alprazolam, Clonazepam, Diazepam, and Lorazepam), tricyclicantidepressants, monoamine oxidase inhibitors, and beta-blockers, andother weight loss agents, including serotonin and noradrenergicre-uptake inhibitors; noradrenergic re-uptake inhibitors; selectiveserotonin re-uptake inhibitors; and intestinal lipase inhibitors.Particular weight loss agents include orlistat, sibutramine,methamphetamine, ionamin, phentermine, bupropion, diethylpropion,phendimetrazine, benzphetermine, and topamax.

In some embodiments, contemplated methods may further comprise assessingone or more indices of on-going weight loss, e.g. the ketone bodyproduction level in a patient; and optionally adjusting the amountadministered; thereby optimizing the therapeutic efficacy of said MetAP2inhibitor.

Formulations

Contemplated administration of Met-AP2 inhibitors in the disclosedmethods include subcutaneous or intravenous administration. For example,injectable preparations are contemplated herein, for example, sterileinjectable aqueous or oleaginous suspensions may be formulated accordingto the known art using suitable dispersing or wetting agents andsuspending agents.

Disclosed or contemplated treatment regimens can include a correctivephase, during which a MetAP2 inhibitor dose sufficient to providereduction of excess adiposity is administered, followed by a maintenancephase, during which a lower or equivalent MetAP2 inhibitor dosesufficient to prevent re-development of excess adiposity may beadministered.

In an embodiment, a pharmaceutically acceptable formulation is providedthat includes a compound 6-O-(4-dimethylaminoethoxy)cinnamoyl fumagillolor pharmaceutically acceptable salts thereof; wherein a single doseadministration of the formulation to a human patient produces a peakplasma concentration (C_(max)) of about 0.5 to about 14 ng/mL, about 0.5to about 6 ng/mL, for example, the peak plasma concentration is about2.1 ng/mL. Further, provided here is a pharmaceutically acceptableformulation is provided that includes a compound6-O-(4-dimethylaminoethoxy)cinnamoyl fumagillol or pharmaceuticallyacceptable salts thereof; wherein a single dose administration of theformulation to a human patient produces a C_(min) about 24 hours afteradministration of about 0 to about 0.3 ng/mL, about 0.0 to about 0.15ng/mL, or about 0.03 to about 0.11 ng/mL, for example, about 0.07 ng/mL,for about 36 hours or less. For example, at 36 hours after a dosageadministration, the plasma concentration in a patient is about 0, orundetectable using standard detection protocols as appreciated by thoseskilled in the art.

For example, provided herein is a pharmaceutically acceptableformulation that includes 6-O-(4-dimethylaminoethoxy)cinnamoylfumagillol or pharmaceutically acceptable salts wherein the single doseadministration (e.g. by subcutaneous or intravenous routes) to a humanproduces a mean area under the curve concentration of the compound of(AUC (0-24 hours) of about 6 ng hr/mL. to about 12 ng hr/mL, 7.5 nghr/mL to about 13.5 ng hr/mL, or about 6 ng hr/mL. to about 15 ng hr/mL,e.g. about 10.5 hr*ng/mL. In an embodiment, the mean area under thecurve concentration of the compound (AUC (0-∞) after administration in apatient is about 6 ng hr/mL. to about 16 ng hr/mL, 7.6 ng hr/mL. toabout 4.4 ng hr/mL, or about 9.3 ng hr/mL. to about 12.7 ng hr/mL, e.g.about 11 ng hr/mL.

EXAMPLES

The examples which follow are intended in no way to limit the scope ofthis invention but are provided to illustrate aspects of the disclosedmethods. Many other embodiments of this invention will be apparent toone skilled in the art. Unless specified, amounts or weights of thecompound refer to the weight of the free base.

Example 1 Less than Weekly Administration of a MetAP2 Inhibitor to ObeseHumans

Obese patients were treated in three cohorts with intravenousadministration of a formulation of the compound6-O-(4-dimethylaminoethoxy)cinnamoyl fumagillol oxalate. The compoundwas intravenously administered to each patient of a cohort (except for aplacebo cohort) twice weekly for 26 days. Each of patients in the threenon-placebo cohorts received either 0.1 mg/m² (cohort 1); 0.3 mg/m²(cohort 2); or 0.9 mg/m² (cohort 3) doses of the compound at the time ofadministration. The trial was conducted under the appropriate governmentand medical supervision.

Weight reduction occurred for 4 days after single administration of 0.9mg/m2 dose, despite terminal half life of the drug of only 5.4 hours(T_(1/2) (H) λz (terminal) is 5.41±2.82 in cohort 3), indicating dailyadministration is not needed. Table 1 summarizes body weightdetermination of the 9 patients in the 0.9 mg/m² cohort on the day ofthe first dose and prior to a second dose administered three or fourdays later.

TABLE 1 Subject Starting Ending Weight Weight No. weight (kg) weight(kg) Change (kg) Change (%) 1 96.3 95.7 −0.6 −0.6 2 101.5 100.4 −1.1−1.1 3 104.6 103.7 −0.9 −0.9 4 102.4 100.5 −1.9 −1.9 5 108.6 107.5 −1.1−1.0 6 107.9 107.9 0 0.0 7 105.5 105 −0.5 −0.5 8 118.7 118 −0.7 −0.6 996 96.2 0.2 0.2 Average 104.6 103.9 −0.7 −0.7 SEM 2.3 2.3 0.0 0.2 P0.004 0.004

Of the 9 subjects treated at the 0.9 mg/m² dose level, 7 patients showedgreater than 3-4 percent body weight loss over 26 days of exposure. FIG.1 depicts the body weight change (loss) as a percent before eachadministration of the twice weekly dose for the 0.9 mg/m² cohort. FIG. 2depicts the Visual Analog Scale reports of hunger decline about 50%following successive biweekly dose administration for the 0.9 mg/m²cohort. As shown in FIGS. 1 and 2, a follow up check at day 36 wasconducted; patients were weighed again at this 36 day mark and theweight loss from the twice weekly regimen over 26 days was substantiallysustained.

The average C_(max) in cohort 3 was 2.1 ng/mL (with a standard deviationof 0.51 ng/mL); average C_(min) was 0.07 ng/mL (SD of 0.04 ng/mL, with ameasured range of 0.014-0.15 ng/mL (including poor responder), and 0.045to 0.15 (excluding poor responder)); average AUC (0-24 hr) was 10.5hour*ng/mL (standard deviation 1.5 hour*ng/mL, measured range 8.57 to13.6 hr*ng/mL) and average AUC (0-∞) was 11 hour*ng/mL (SD 1.7hour*ng/mL). FIG. 3 depicts exposure of drug as function of dose withmeasurements taken at 5 min and 60 min post dose on each of several daysof twice-weekly administration over a 26 day period, and shows that drugexposure stabilizes by the third or fourth dose administered.

There was a significant correlation between weight loss of patients andmaintained exposure of 0.02 ng/mL of the drug above the level ofquantitation of the assay 24 hours after dosing, as shown in FIG. 4(circled data point is exposure of one poor responder below the level ofquantitation of assay). The PK profile at day 26 is representative ofsteady state (see FIG. 5). Lack of efficacy at 0.1 and 0.3 mg/m²supports maintaining drug exposure above 0.02 ng/mL at 24 hours postdose, but with no drug exposure 36 hours after dosing.

Example 2 Correlation of Effective Dose and Excess Body Weight

All of the subjects of the trial described in Example 1 received dosesranging from 1.8 to 2.2 mg with each administration (given twiceweekly). However, weight change was not strictly associated with dosedelivered. Instead, response was strongly associated with doseadministered per unit excess body weight, as compared to weight changeassociated with dose delivered per unit body weight. FIG. 6 indicatesthe body weight change of patients in the combined 0.1 and 0.3 mg/m²cohorts vs. dose of compound in μg per kg excess weight of patient, andindicates that exceeding approximately 40 μg of drug per kg of excessbody weight may be important in order to see effects in obese patients.

This correlation may be due to obtaining the drug effect at least inpart by exposure of the drug to adipose tissue. This indicates thatdosing appropriately with a MetAP2 inhibitor surprisingly requiresconsideration of a patient's excess weight (instead of total weight),given that drug exposures (drug amount) were not substantially differentbetween subjects and both the vasculature and liver were dosedequivalently, but weight loss differed.

FIG. 7 indicates that weight loss efficacy is obtained at doses of ˜20μg/kg, and above, administered twice weekly.

Example 3 Adiponectin Levels

Levels of adiponectin in the serum of patients undergoing the trial werealso measured. Adiponectin concentrations were markedly increased (byover 60%, see FIG. 8) with treatment, also pointing to the importance ofadipose as a target for the drug since adiponectin is produced by fatcells. FIG. 8 also indicates that there is a strong correlation betweenadiponectin changes and excess weight loss.

FIG. 9 indicates the changes in the ratio of two adipocyte factors(leptin and adiponectin) for subjects in the 0.3 and 0.9 mg/m² cohortsafter 26 days of the trial. The effect of treatment on the ratio ofleptin to adiponectin appears to be a particularly strong predictor ofweight. Combined, these observations appear to indicate that adiposetissue is a critical target related to weight loss, and that targetingfat tissue for MetAP2 inhibitors or dosing to achieve optimal fat tissueexposure is important.

Example 4 Toxicity Studies

A testis toxicity study was performed using daily subcutaneousadministration or every other day (every third day) subcutaneousadministration in rats. 1 mg/kg of 6-O-(4-dimethylaminoethoxy)cinnamoylfumagillol oxalate (Compound) was administered daily and compared toevery third day with the same dose. Additionally, equivalent totalexposure using a 3 mg/kg dose administered every third day was comparedas well.

64 Sprague-Dawley male rats within ±20% of mean body weight atinitiation of dosing were used for the study. Vehicle control orCompound was administered once daily or every 3^(rd) day for 4 weeks, ata volume of 5 mL/kg, as follows, with groups 1-4 for toxicity and groups5-8 for toxicokinetic studies.

Dose Volume Dose Group Sex Number Dose Frequency (mL/kg) (mg/kg) 1 Male10 Daily 5 0 2 Male 10 Daily 5 1 3 Male 10 Every 3^(rd) day 5 1 4 Male10 Every 3^(rd) day 5 3 5 Male 6 Daily 5 0 6 Male 6 Daily 5 1 7 Male 6Every 3^(rd) day 5 5 8 Male 6 Every 3^(rd) day 5 3

Upon completion of the study, complete necropsy examinations areperformed, and the seminal vesicle, testes, and other organs are weighedat terminal necropsy. Terminal body weights are determined just prior tonecropsy for assessment of organ weight changes.

Organ weight changes are shown in Table 2 and FIG. 10.

TABLE 2 Relative Absolute Relative to to Brain Group weight Body weightWeight Organ mg/kg (g) (%) (%) Thymus 0 0.397 0.100 18.85 1 0.343 0.10316.65 1 every 3^(rd) day 0.421 0.106 20.30 3 every 3^(rd) day 0.4230.110 20.32 Seminal Vesicles 0 1.524 0.387 72.44 1 1.201** 0.360 58.47 1every 3^(rd) day 1.523 0.385 73.41 3 every 3^(rd) day 1.491 0.390 71.67Prostate 0 0.658 0.167 31.38 1 0.546 0.163 26.59 1 every 3^(rd) day0.710 0.179 34.13 3 every 3^(rd) day 0.663 0.172 31.88 Epididymides 01.278 0.324 60.75 1 1.130 0.338 55.30 1 every 3^(rd) day 1.249 0.31760.09 3 every 3^(rd) day 1.267 0.331 60.80 Testes 0 3.080 0.781 146.41 12.569* 0.769 125.72 1 every 3^(rd) day 3.097 0.786 149.04 3 every 3^(rd)day 3.273 0.856 157.22 *Significant (p < 0.05) **Significant (p < 0.01)

As FIG. 10 shows, no tissue weight effects (testes and seminal vesicleweights) are observed in animals administered with less frequent dosing,indicating minimal or no testicular toxicity.

Table 3 shows the surprising findings from the study comparing 1mg/kg/day dose with 1 mg/kg and 3 mg/kg every three days. While the 1mg/kg/day dose indicates adverse findings (e.g. blood dyscrasias and/orirreversible testis lesions); the 3 mg/kg every three days does not showany significant adverse findings while reduces animal weightsignificantly, and increases the therapeutic window over prior findingsusing daily administration. The injection site tolerability appears tobe acceptable even at doses up to 6 mg.

TABLE 3 3 mg/kg Findings 1 mg/kg/day 1 mg/kg Q3D Q3D* Hematology Reducedblood cell counts No findings No findings WBC (0.68X), Lymphocyte(0.65X) Neutrophil (0.83X), Monocyte (0.79X), Eosinophil (0.75X),Basophil (0.55X), Large unstained cell (0.67X) Clinical ChemistryReduced alk phos (0.72X) No findings Higher albumin/ Reduced Inorgphosphate (0.96 X) globulin Higher albumin/globulin (1.12X) (1.09X)Higher potassium (1.2X) Organ weight Altered organ weights: No findingsNo findings Testes (0.83X), Epididymides (0.88X) Prostate (0.83X),Seminal vesicle (0.79X), Spleen (0.71X), Liver 0.85X, Salivary gland(0.87X), Thymus (0.86X), Thyroid (0.82X), Brain 1.15X, Adrenal (1.24X)Macroscopic Smaller testes and epididymides No findings No findingsMicroscopic Germ cell depletion/degeneration 9/10 No findings Nofindings Hypospermia (majority) Lymph node atrophy QD: DailyAdministration; Q3D: every third day administration

INCORPORATION BY REFERENCE

References and citations to other documents, such as patents, patentapplications, patent publications, journals, books, papers, webcontents, have been made throughout this disclosure. All such documentsare hereby incorporated herein by reference in their entirety for allpurposes.

EQUIVALENTS

Various modifications of the invention and many further embodimentsthereof, in addition to those shown and described herein, will becomeapparent to those skilled in the art from the full contents of thisdocument, including references to the scientific and patent literaturecited herein. The subject matter herein contains important information,exemplification and guidance that can be adapted to the practice of thisinvention in its various embodiments and equivalents thereof.

What is claimed is:
 1. A method for treating obesity in a human patienthaving an initial body mass index at least about 30 kg/m², or at leastabout 27 kg/m² and suffering from weight related co-morbidity, and inneed thereof, comprising parenterally administering once or twice weeklyto said patient about 20 μg to about 80 μg, per kg of excess adiposetissue of the patient, of 6-O-(4-dimethylaminoethoxy)cinnamoylfumagillol or pharmaceutically acceptable salts thereof.
 2. The methodof claim 1, comprising administering about 40 μg to about 80 μg per kgof excess body weight of the patient, of6-O-(4-dimethylaminoethoxy)cinnamoyl fumagillol or pharmaceuticallyacceptable salts thereof.
 3. The method of claim 1, wherein parenterallyadministering is subcutaneously administering.
 4. The method of claim 1,wherein parenterally administering is intravenously administering. 5.The method of claim 1, wherein administering to the patient once ortwice weekly is repeated until a desired weight is achieved.
 6. A methodfor treating obesity in a human patient having an initial BMI of 30kg/m² or more, comprising subcutaneously administering, once or twiceweekly, about 30 μg to about 90 μg per kg of excess adipose tissue ofthe patient, 6-O-(4-dimethylaminoethoxy)cinnamoyl fumagillol orpharmaceutically acceptable salts thereof.